The Phage-shock-protein (PSP) Envelope Stress Response: Discovery of Novel Partners and Evolutionary History

Abstract The phage shock protein (PSP) systems orchestrate a conserved bacterial stress response function by stabilizing the cell membrane and protecting bacteria from envelope stress. However, the full repertoire of PSP components remains poorly characterized. We combined comparative genomics and protein sequence-structure-function analyses to systematically identify sequence homologs, phyletic patterns, domain architectures, and gene neighborhoods to trace the evolution of PSP components across the tree of life. We showed that different bacterial clades possess distinct PSP systems. This integrative approach traced the universal nature and origin of PspA/Snf7 (Psp/ESCRT systems) to the Last Universal Common Ancestor. We identified novel partners of the PSP system: one is the Toastrack domain, which likely facilitates assembling diverse sub-membrane stress-sensing and signaling complexes; another is the HAAS–PadR-like transcription factor system. We showed that PspA/Snf7 proteins have evolved associations with ATP-dependent, CesT/Tir-like chaperones, and Band-7 domain proteins to mediate sub-membrane dynamics. Our work also uncovered links between the PSP components and diverse SHOCT-like domains, suggesting a role in assembling membrane-associated complexes of proteins with disparate biochemical functions. Tracing the evolution of Psp cognate proteins provides new insights into the functions of the system and helps predict previously uncharacterized, often lineage-specific, membrane-dynamics and stress response systems. The conservation of PSP systems across bacterial phyla emphasizes the importance of this stress response system in prokaryotes, while its modularity in various lineages indicates adaptation to lineage-specific cell-envelope structures, lifestyles, and adaptation mechanisms. The results can be accessed at https://jravilab.shinyapps.io/psp-evolution.